- 2009. longitudinal assessment of neuropsychological function in major depression

© 2009 The Royal Australian and New Zealand College of Psychiatrists

Longitudinal assessment of neuropsychological function in major depression

Katie M. Douglas, Richard J. Porter

Neuropsychological impairment is a core component of major depression, yet its relationship to clinical state is unclear. The aims of the present review were to determine which neuropsychological domains and tasks were most sensitive to improvement in clinical state in major depression and to highlight the methodological issues in such research. Studies that included a baseline and at least one follow-up neuropsychological testing session in adults with major depression were identifi ed using MEDLINE, Web of Science and ScienceDirect databases. Thirty studies were included in the review. Findings in younger adult populations suggested that improvement in mood was most strongly related to improved verbal memory and verbal fl uency, while measures of executive functioning and attention tended to remain impaired across treatment. In late-life major depression, improved psychomotor speed was most closely related to treatment response, but there was much inconsistency between study fi ndings, which may be due to methodological issues. In major depression, particular neuropsychological domains are more strongly related to clinical state than others. The fi ndings from the present review suggest that the domains most sensitive to clinical state are verbal learning and memory, verbal fl uency and psychomotor speed. In contrast, measures of attention and executive functioning perhaps represent more trait-like markers of major depression. With further methodologically sound research, the changes in neuropsychological function associated with treatment response may provide a means of evaluating different treatment strategies in major depression.Key words: executive function, major depressive disorder, memory, neuropsychological function, remission.

Australian and New Zealand Journal of Psychiatry 2009; 43:1105–1117

Richard J. Porter, Professor (Correspondence); Katie M. Douglas, PhD Candidate

Department of Psychological Medicine, University of Otago, Christchurch, PO Box 4345, Christchurch, New Zealand. Email: [email protected]

Received 14 June 2009; accepted 13 August 2009.

Among the many disabling features of major depressive disorder (MDD) is neuropsychological dysfunction, which is increasingly becoming recognized as a core component of the disorder [1]. A fundamental question regarding this neuropsychological dysfunction is whether

it is part of the underlying and stable neurobiological vulnerability to MDD (i.e. a trait) or whether it occurs only during episodes of depressed mood (i.e. state). Alternatively, it is possible that functions subserved by certain areas of the brain may be more sensitive to clini-cal state, while other functions are less changeable but more clearly trait-related.

Longitudinal description of the pattern of neuropsy-chological impairment in MDD during episodes, and during and following treatment may help to answer these fundamental questions. In addition, longitudinal assess-ment would be useful for the following reasons. First, it

000095824

Nota adhesiva

Douglas, K. M., & Porter, R. J. (2009). Longitudinal assessment of neuropsychological function in major depression. Australian & New Zealand Journal Of Psychiatry, 43(12), 1105-1117. doi:10.3109/00048670903279887

1106 K.M. DOUGLAS, R.J. PORTER

Exclusion criteria

Reasons for exclusion were: (i) use of a depressed sample with

comorbid major medical, neurological, or endocrinological conditions

(the number of studies in this criterion is unknown because many stud-

ies of disorders such as dementia or Parkinson’s disease involve comor-

bid depression); (ii) inclusion of patients who were being treated with

electroconvulsive therapy (ECT; a review of all papers conducting

follow-up neuropsychological testing in ECT patients has previously

been published [2]); (iii) lack of comparison of change in neuropsycho-

logical function between test occasions (n = 3); or (iv) lack of presen-

tation of results for described neuropsychological testing procedures

(n = 2). For the latter exclusion condition, the authors were contacted

via email and asked to send their neuropsychological data, but no

replies were received. All studies were limited to English-language

publications.

Results

Study characteristics

Thirty studies met the inclusion criteria (Table 1). Of these studies, 18

included healthy controls but two of these studies only tested the con-

trols at baseline [3,4]. The analyses conducted in these studies were

able to be categorized under fi ve main headings (some studies included

more than one type of analysis), as follows.

(1) Those that measured overall change in mood rating scales and

overall change in neuropsychological function, but did not report the

direct relationship between these two measures [5–9]. In the Majer

et al. and Reppermund et al. studies, patients had been classed as

remitters versus non-remitters (and responders vs non-responders), but

this information was used only for baseline neuropsychological com-

parisons and predictions [6,7].

(2) Those in which all or nearly all patients were deemed to be remit-

ters (or responders) at follow up. For these studies, the change in neu-

ropsychological function over time was presented and, in some cases,

compared with healthy controls [10–16].

(3) Those in which only the neuropsychological performance of the

remitters (or responders) was presented and, in some cases, compared

with healthy controls and/or the depressed group as a whole [3,17–21].

(4) Those that categorized patients into remitters (or responders) and

non-remitters (or non-responders) and compared the change in neurop-

sychological function between the two groups over time [3,4,21–28].

(5) Those that correlated change in mood rating scales with change

in neuropsychological performance over time [3,18,21,29–32].

The latter two types of studies are more informative than the others

when examining the association between treatment response and

changes in neuropsychological function. Thus, more of an emphasis

will be placed on these studies in the review. The results from the review

(Table 1) will be discussed in detail in the subsequent sections, followed

by a discussion of the methodological inconsistencies between these

studies.

may further elucidate changes in brain function in MDD both during episodes and following recovery. Second, measuring changes in neuropsychological function may be helpful in assessing the effects of various treatments including both pharmacological and psychological. Measuring neuropsychological changes could provide a more objective marker of treatment response and may show change or differentiation between treatments at an earlier time point than traditional depression rating scales. The ability to measure response or non-response to treatment at an early stage could potentially also enable clinicians to either increase dosing or alter treat-ment in order to determine the best treatment for the patient as quickly as possible.

The aims of the present review were therefore as fol-lows: (i) to examine change in neuropsychological func-tion in MDD and its relationship to symptomatology and to further examine which domains of function appear to be sensitive to improvement in clinical state; (ii) to exam-ine which neuropsychological domains or tests would be most likely to be useful in determining treatment response in MDD; and (iii) to examine methodological issues in studies examining change in neuropsychological func-tion over time in MDD.

We reviewed all available literature in which neurop-sychological testing and clinical measures of severity of MDD at baseline and after a specifi ed amount of time after treatment, were conducted.

Methods

Search strategy

Up to 1 May 2009, electronic database searches were carried out

for relevant papers, utilizing MEDLINE and Web of Science. In the

initial search, the terms: ‘major depressive disorder’ or ‘major

depression’ or ‘depression’ and ‘neuropsychological impairment’ or

‘neuropsychological function’ or ‘cognitive impairment’ or ‘cogni-

tive function’ were used. To enable the inclusion of more recent

articles, ScienceDirect was also searched using the aforementioned

keywords in the ‘abstract, title, keywords’ fi eld. We also checked the

reference lists of all the relevant papers and the Web of Science was

used to review the articles that had cited the relevant articles found

using these search strategies.

Inclusion criteria

We selected only those articles involving assessment of neuropsy-

chological function and depression severity at least twice during treat-

ment of a major depressive episode (unipolar or bipolar) in younger

adult or late-life samples.

NEUROPSYCHOLOGICAL CHANGE IN MDD 1107T

able

1.

Rev

iew

ed s

tudi

es

Stu

dy

nTy

pe

of

MD

D

Bas

elin

em

oo

dra

tin

gA

ge

(yea

rs)

Fo

llow

up

Trea

tmen

t o

utc

om

em

easu

res

Su

mm

ary

of

mai

n fi

nd

ing

s

Dep

ress

ed a

dul

t st

udie

s

Beblo

et

al.

(1999)

[22]

P =

41

C =

20

• M

DD

• In

patient

BD

I =

25

CD

S =

14

MA

DR

S =

16

P =

56

C =

56

1–3 m

onth

sR

esponse (

n =

12

)

<17 o

n B

DI

and

≥50%

reduction o

n

BD

I at

FU

.

Response:

sig

nifi

cant

impro

vem

ent

in d

esig

n,

phonolo

gic

al and v

erb

al fl uency c

om

pare

d t

o

non-r

esponders

.

Bir

inger

et a

l. (2

005,2

007)

[21,3

]

P =

30

C =

50

• U

NI

MD

D

• In

patient/

outp

atient

HD

RS

-17 =

22

P =

35

C =

35

2 y

ears

Corr

ela

tion

betw

een Δ

HD

RS

+

Δ n

euro

psy

c.

Recove

ry (

n =

17)

≤7 o

n H

DR

S a

t F

U.

2005 a

naly

sis

: sig

nifi

cant

corr

ela

tion b

etw

een

Δ H

DR

S a

nd Δ

com

posite s

core

on e

xecutive

functionin

g.

Recove

ry:

exe

cutive

functionin

g im

pro

ved t

o

leve

l of

contr

ols

exc

ept

Str

oop t

ask a

nd

sem

antic fl

uency.

2007 r

e-a

naly

sis

: sig

nifi

cant

corr

ela

tion

betw

een Δ

HD

RS

and Δ

verb

al m

em

ory

but

not

attention (

exe

cutive

function),

vis

ual

mem

ory

or

psychom

oto

r speed.

Recove

ry:

impro

vem

ent

in v

erb

al m

em

ory

to

contr

ol le

vel at

FU

and p

erf

orm

ed b

etter

than

in t

heir d

epre

ssed s

tate

in a

ttention,

vis

ual

mem

ory

and p

sychom

oto

r speed.

Consta

nt

et a

l. (2

005)

[29]

P =

20

C =

26

• U

NI

MD

D

• N

on-p

sychotic

• O

utp

atient

BD

I =

26

P =

48

C =

49

3 w

eeks

7 w

eeks

Corr

ela

tion

betw

een Δ

BD

I and

Δ n

euro

psy

c.

Com

pari

son o

f

‘more

depre

ssed’

vs ‘le

ss d

epre

ssed’

at

FU

.

Sig

nifi

cant

corr

ela

tion b

etw

een Δ

BD

I score

and Δ

psychom

oto

r speed o

n S

troop t

ask

betw

een b

aselin

e a

nd 3

weeks in d

epre

ssed

gro

up. N

o f

urt

her

Δ a

t 7 w

eeks.

More

inte

rfere

nce f

or

word

s w

ith n

egative

vale

nce in ‘m

ore

depre

ssed g

roup’ vs ‘le

ss

depre

ssed’ gro

up.

Galla

gher

et a

l. (2

007)

[23]

P =

25

C =

13

• U

NI

MD

D

• N

on-p

sychotic

• O

utp

atient

BD

I =

29.3

HD

RS

-17 =

21

MA

DR

S =

29

P =

33

C =

31

2–6 m

onth

sR

em

issio

n (

n =

11)

<8 o

n H

DR

S a

t F

U.

Rem

issio

n:

gre

ate

r im

pro

vem

ent

in v

erb

al

decla

rative

mem

ory

com

pare

d t

o t

hose w

ho

rem

ain

ed d

epre

ssed a

t F

U.

Herr

era

-

Guzm

an

et

al.

(2008)

[28]

P =

20

• U

NI

MD

D

• N

on-p

sychotic

• O

utp

atient

HD

RS

-17 =

25

P =

24

8 w

eeks

Response (

n =

12)

>50%

reduction o

n

HD

RS

at

FU

Response:

sig

nifi

cant

gre

ate

r im

pro

vem

ent

in

vis

ual m

em

ory

than n

on-r

esponders

(responders

were

wors

e t

o b

egin

with).

Jaeger

et a

l. (2

006)

[5]

P =

48

• M

DD

• In

cl.

psy

chotic

• In

patient

HD

RS

-17 =

16

P =

40

6 m

onth

sG

roup im

pro

vem

ent

on H

DR

S s

core

at

FU

.

Impro

vem

ent

at

FU

in d

om

ain

s o

f attention,

work

ing m

em

ory

, and w

ord

fl u

ency.

No

analy

sis

of

corr

ela

tion b

etw

een t

hese

impro

vem

ents

and Δ

HD

RS

score

done.

(Con

tinue

d)


Tab

le 1

. (C

onti

nued

)

Stu

dy

nTy

pe

of

MD

D

Bas

elin

em

oo

dra

tin

gA

ge

(yea

rs)

Fo

llow

up

Trea

tmen

t o

utc

om

em

easu

res

Su

mm

ary

of

mai

n fi

nd

ing

s

Maje

r et

al.

(2004)

[6]

P =

73

• U

NI

or

BD

MD

D

• In

cl.

psy

chotic

• In

patient

HD

RS

-21 =

29

MA

DR

S =

34

BD

I =

26

P =

46

Appro

x. 4 w

eeks

6 m

onth

s

Response

(n =

35)

= 5

0%

reduction o

n H

DR

S

at

FU

. R

em

issio

n

(n =

39)

<10 o

n

HD

RS

at

FU

.

As a

gro

up,

depre

ssiv

e r

atings w

ere

sig

nifi

cantly r

educed a

t F

U,

yet

no c

hange in

neuro

psyc w

ith e

xception o

f im

pro

ved

perf

orm

ance o

n t

he letter

cancella

tion t

ask.

Cla

ssifi

cation o

f re

sponse/r

em

issio

n u

sed t

o

com

pare

baselin

e n

euro

psyc o

nly

.

Neu e

t al

.

(2001)

[30]

P =

80

C =

62

• M

DD

incl.

UN

I,

BD

, D

YS

and

schiz

.AD

• In

patient

BR

MS

:

UN

I =

20,

BP

= 1

7,

DY

S =

17,

schiz

.AD

= 1

9

P =

47

C =

52

Appro

x.

3 m

onth

s

Corr

ela

tion

betw

een Δ

BR

MS

and Δ

neuro

psy

c.

No c

orr

ela

tion:

Δ B

RM

S +

Δ a

ny c

ognitiv

e

dom

ain

s (

verb

al and v

isual le

arn

ing a

nd

mem

ory

, ve

rbal fl uency,

psychom

oto

r speed).

Repperm

und

et a

l. (2

007)

[24]

P =

75

• M

DD

• In

patient

HD

RS

-21 =

25

P =

45

1–3 m

onth

sR

em

issio

n (

n =

51)

≤9 o

n H

DR

S a

t F

U.

Rem

issio

n:

sig

nifi

cant

impro

vem

ent

in

psychom

oto

r speed c

om

pare

d t

o n

on-

rem

issio

n g

roup.

Repperm

und

et a

l. (2

009)

[7]

P =

53

C =

13

• U

NI

MD

D

• In

patient

HD

RS

-21 =

25

P =

44

C =

46

Appro

x. 9 w

eeks

6 m

onth

s

Rem

issio

n (

n =

43)

≤9 o

n H

DR

S a

t F

U.

After

corr

ecting f

or

pra

ctice e

ffects

, w

as

sig

nifi

cant

impro

vem

ent

in s

om

e e

xecutive

functionin

g t

ests

(ve

rbal and s

em

antic

fl uency,

work

ing m

em

ory

). C

lassifi

cation o

f

rem

issio

n u

sed t

o c

om

pare

baselin

e

neuro

psyc o

nly

.

Tri

chard

et

al.

(1995)

[31]

P =

23

C =

15

• U

NI

or

BD

MD

D

• In

patient

MA

DR

S =

39

P =

47

C =

41

4 w

eeks

Corr

ela

tion

betw

een Δ

MA

DR

S

and Δ

neuro

psy

c

(all

euth

ym

ic a

t

FU

).

Sig

nifi

cant

corr

ela

tion:

Δ M

AD

RS

+ Δ

verb

al

fl uency.

Depre

ssed g

roup’s

perf

orm

ance o

n

verb

al fl uency r

eached t

hat

of

contr

ols

after

successfu

l tr

eatm

ent. P

erf

orm

ance o

n S

troop

task r

em

ain

ed s

ignifi

cantly w

ors

e t

han

contr

ols

.

Vyth

ilingam

et a

l. (2

004)

[10]

P =

22

C =

33

• U

NI

MD

D

• O

utp

atient

YD

I =

34

P =

41

C =

34

7 m

onth

sR

esponse (

all)

= Δ

in Y

DI

score

.

Response:

sig

nifi

cant

impro

vem

ent

in v

erb

al

mem

ory

.

Wro

olie

et

al.

(2006)

[11]

P =

17

• U

NI

MD

D

• N

on-p

sychotic

• O

utp

atient

• F

em

ale

s o

nly

HD

RS

-21 =

21

P =

56

3 m

onth

sR

em

issio

n (

n =

15)

≤7 o

n H

DR

S a

t F

U.

Sig

nifi

cant

impro

vem

ent

at

FU

testing f

ound

in im

media

te v

erb

al and v

isual m

em

ory

(both

usin

g t

he W

MS

-III)

and e

xecutive

functionin

g

(TM

T-B

). N

o s

epara

tion b

etw

een r

em

issio

n

and n

on-r

em

issio

n.

NEUROPSYCHOLOGICAL CHANGE IN MDD 1109

Tab

le 1

. (c

onti

nued

)

Stu

dy

nTy

pe

of

MD

D

Bas

elin

em

oo

dra

tin

gA

ge

(yea

rs)

Fo

llow

up

Trea

tmen

t o

utc

om

em

easu

res

Su

mm

ary

of

mai

n fi

nd

ing

s

Young e

t al

.

(2004)

[8]

P =

19

• B

D w

ith

resid

ual M

DD

sym

pto

ms (

17

with c

urr

ent

MD

D)

• O

utp

atient

HD

RS

-17 =

18

MA

DR

S =

23

P =

49

3 w

eeks

6 w

eeks

Δ H

DR

S a

nd Δ

MA

DR

S s

core

s

from

baselin

e.

Sym

pto

ms o

f M

DD

and p

erf

orm

ance o

n

tasks o

f spatial w

ork

ing a

nd r

ecognitio

n

mem

ory

and v

erb

al fl uency im

pro

ved

com

pare

d t

o p

lacebo. N

o a

naly

sis

of

corr

ela

tion b

etw

een Δ

HD

RS

or

Δ M

AD

RS

and Δ

neuro

psyc d

one.

Zobel et

al.

(2004)

[25]

P =

64

• U

NI

MD

D

• N

on-p

sychotic

• In

patient

HD

RS

-17 =

25

P =

47

4 w

eeks

Corr

ela

tion

betw

een Δ

HD

RS

and Δ

neuro

psy

c.

No c

orr

ela

tion:

Δ H

DR

S +

Δ a

ny c

ognitiv

e

dom

ain

s (

verb

al le

arn

ing a

nd m

em

ory

and

attention).

Dep

ress

ed la

te-li

fe s

tud

ies

Abas e

t al

.

(1990)

[12]

P =

20

C =

20

• E

ndogenous

MD

D/B

D

• In

patient/

outp

atient

• S

am

ple

>60 y

ears

• 10 h

ad o

nset

<50 y

ears

MA

DR

S =

31

P =

70

C =

68

Recove

ryR

ecove

ry (

all)

, as

deem

ed b

y

psy

chia

tris

t and

rela

tive

s.

Recove

ry:

sig

nifi

cant

impro

vem

ent

on p

attern

recognitio

n a

nd K

endri

ck O

bje

ct

Learn

ing

Task a

ccura

cy t

o leve

l of

contr

ols

.

Beats

et

al.

(1996)

[13]

P =

19

C =

15

• M

DD

• In

patient/

outp

atient

• S

am

ple

>60 y

ears

• 7 h

ad o

nset

<60 y

ears

MA

DR

S =

40

HD

RS

-17 =

30

P =

72

C =

69

Recove

ryR

ecove

ry (

all)

<10

on M

AD

RS

.

Recove

ry:

impro

vem

ent

acro

ss a

ll ta

sks

(attention,

exe

cutive

functionin

g,

pro

cessin

g

speed,

vis

uospatial le

arn

ing a

nd m

em

ory

) to

leve

l of

contr

ols

exc

ept

for

som

e late

ncy/

reaction t

ime m

easure

s.

Bhalla

et

al.

(2006)

[14]

P =

56

C =

40

• U

NI

MD

D

• N

on-p

sychotic

• In

patient/

outp

atient

• S

am

ple

>60 y

ears

HD

RS

-17 =

20

P =

72

C =

70

1 y

ear

Rem

issio

n (

all)

≤10

on H

DR

S.

Patients

im

pro

ved t

o t

he s

am

e e

xte

nt

as

contr

ols

in a

ll fi ve

neuro

psyc d

om

ain

s,

still

rem

ain

ing b

elo

w c

ontr

ols

at

FU

.

Rem

issio

n:

45%

of

patients

cognitiv

ely

impaired a

t 1 y

ear

com

pare

d w

ith 3

0%

at

baselin

e. Im

pair

ment

gre

ate

st

in v

isuospatial

abili

ty,

info

rmation-p

rocessin

g s

peed a

nd

dela

yed m

em

ory

.

(Con

tinue

d)

1110 K.M. DOUGLAS, R.J. PORTERT

able

1.

(Con

tinu

ed)

Stu

dy

nTy

pe

of

MD

D

Bas

elin

em

oo

dra

tin

gA

ge

(yea

rs)

Fo

llow

up

Trea

tmen

t o

utc

om

em

easu

res

Su

mm

ary

of

mai

n fi

nd

ing

s

Bu

tte

rs e

t al

.

(2000)

[15]

P =

45

C =

20

• M

DD

• In

patient/

outp

atient

• Late

-life

patients

HD

RS

-17 =

22

P =

73

C =

70

12 w

eeks

Rem

issio

n (

all)

≤10

on H

DR

S f

or

3 w

eeks.

Rem

issio

n:

sm

all

impro

vem

ent

in D

RS

ove

r

treatm

ent

due t

o s

mall

changes a

cro

ss

subscale

s,

not

sig

nifi

cant

impro

vem

ent

on 1

dom

ain

. O

n r

em

issio

n,

perf

orm

ance s

till

belo

w c

ontr

ols

.

Bu

tte

rs e

t al

.

(2004):

Stu

dy

I [2

6]

P =

53

• M

DD

• In

patient/

outp

atient

• S

am

ple

>65 y

ears

HD

RS

-17 =

22

P =

72

12–14 w

eeks

Recurr

ence (

n =

8)

DS

M-I

V M

DD

and

≥15 H

DR

S f

or

3 w

eeks.

Recurr

ence:-

did

not

diff

er

on t

ota

l D

RS

at

baselin

e o

r after

treatm

ent

response,

or

on

any s

ubscale

s c

om

pare

d w

ith n

on-

recurr

ence.

Deva

nand

et a

l. (2

003)

[27]

P =

26

• U

NI

MD

D

• O

utp

atient

• S

am

ple

>50 y

ears

HD

RS

-17 =

15

CG

I =

3.4

P =

72

12 w

eeks

Response (

n =

17)

≥50%

declin

e o

n

HD

RS

and C

GI

= 1

or

2.

Response:

impro

vem

ent

on D

SS

T w

ith

sert

ralin

e b

ut

declin

e in n

on-r

esponders

.

Diff

ere

nce b

etw

een g

roups s

ignifi

cant

Dora

isw

am

y

et a

l. (2

003)

[32]

P =

444

• U

NI

MD

D

• N

on-p

sychotic

• O

utp

atient

• S

am

ple

>60 y

ears

HD

RS

-24 =

25

P =

68

12 w

eeks

Corr

ela

tion

betw

een Δ

HD

RS

and Δ

neuro

psy

c.

Sig

nifi

cant

corr

ela

tion:

Δ H

DR

S a

nd Δ

DS

ST

and Δ

SLT

for

patients

tre

ate

d w

ith s

ert

ralin

e

and n

ort

ripty

line,

but

not

for

patients

tre

ate

d

with fl

uoxe

tine. C

orr

ela

tion w

as s

trongest

for

sert

ralin

e.

Galla

ssi et

al.

(2006)

[17]

P =

42

C =

15

• M

DD

• O

utp

atient

• S

am

ple

>50 y

ears

• A

ll la

te-o

nset

HD

RS

= 2

6

GD

S =

25

P =

68

C =

69

6 m

onth

sR

em

issio

n (

n =

33

)

≤11

on H

DR

S f

or

those o

ver

65 y

ea

rs

and ≤

7 f

or

those

under

65 a

t F

U.

Rem

issio

n: im

pro

vem

ent

on M

MS

E a

nd v

erb

al

and v

isual m

em

ory

at

FU

but

stil

l diff

ere

d f

rom

contr

ols

in a

few

tasks r

equirin

g m

ore

cogniti

ve

effo

rt (

logic

al m

em

ory

and a

ssocia

ted v

erb

al

learn

ing). R

em

itters

not

com

pare

d t

o n

on-

rem

itters

on n

euro

psy

c f

unctio

ns.

Lee e

t al

.

(2007)

[16]

P =

67

• U

NI

MD

D

• O

utp

atient

• S

am

ple

>60 y

ears

MA

DR

S =

21

P =

68

1 y

ear

Rem

issio

n (

all)

<9

on M

AD

RS

at

FU

.

Rem

issio

n:

55%

of

patients

had M

CI

at

baselin

e a

nd 4

5%

of

patients

still

had M

CI

at

FU

.

Nebes e

t al

.

(2000)

[18]

P =

39

C =

19

• U

NI

MD

D

• N

on p

sychotic

• In

patient/

outp

atient

HD

RS

-17 =

23

P =

71

C =

70

12 w

eeks

Rem

issio

n (

n =

20

)

≤10 o

n H

DR

S f

or

3

consecutive

weeks.

Corr

ela

tion b

etw

een

Δ H

DR

S a

nd Δ

neuro

psy

c.

Rem

issio

n:

impro

vem

ent

on t

asks o

f w

ork

ing

mem

ory

and p

rocessin

g s

peed. B

ut

am

ount

of

impro

vem

ent

was n

o g

reate

r th

an t

hat

seen in c

ontr

ols

with r

epeat

testing. N

on-

rem

itters

were

not

rete

ste

d o

n n

euro

psyc

tasks. N

o c

orr

ela

tion:

Δ H

DR

S a

nd Δ

work

ing

mem

ory

or

Δ p

rocessin

g s

peed in r

em

itters

.


Tab

le 1

. (C

onti

nued

)

Stu

dy

nTy

pe

of

MD

D

Bas

elin

em

oo

d r

atin

gA

ge

(yea

rs)

Fo

llow

up

Trea

tmen

t o

utc

om

em

easu

res

Su

mm

ary

of

mai

n fi

nd

ing

s

Nebes e

t al

.

(2003)

[19]

P =

73

C =

21

• U

NI

MD

D

• N

on-p

sychotic

• In

patient/

outp

atient

• 41 late

-onset

MD

D

HD

RS

-17 =

23

P =

70

C =

71

1,4

,6,1

2 w

eeks

Response (

n =

32)

≤10 o

n H

DR

S a

t

FU

.

Response –

no im

pro

vem

ent

in c

ognitiv

e

perf

orm

ance a

fter

response t

o a

ntidepre

ssant

thera

py.

Responders

not

directly c

om

pare

d t

o

non-r

esponders

.

O’B

rien e

t al

.

(2004)

[20]

P =

61

C =

40

• M

DD

and B

D

• In

cl.

psy

chotic

• In

patient/

outp

atient

• S

am

ple

>60 y

ears

MA

DR

S =

31

P =

74

C =

73

6 m

onth

sR

em

issio

n (

n =

26

)

<8 o

n M

AD

RS

an

d

not

DS

M-I

V M

DD

.

Rem

issio

n:

defi cits in a

ttention,

work

ing

mem

ory

, vis

ual and v

erb

al le

arn

ing a

nd

mem

ory

, and e

xecutive

functionin

g p

ers

iste

d

at

6 m

onth

s. T

his

was t

he s

am

e t

rend a

s t

he

whole

depre

ssed g

roup a

t 6 m

onth

s

(rem

itters

and n

on-r

em

itters

) com

pare

d t

o

contr

ols

. N

o c

om

pari

son b

etw

een r

em

itters

and n

on-r

em

itters

was c

onducte

d.

Port

ella

et

al.

(2003)

[4]

P =

30

C =

15

• U

NI

MD

D

• In

patient/

outp

atient

• S

am

ple

>60 y

ears

HD

RS

-17 =

30

P =

72

C =

60

1 y

ear

Rem

issio

n (

n =

21)

<8 o

n H

DR

S a

t F

U.

Rem

issio

n:

no Δ

neuro

psyc f

unction o

ver

12 m

onth

s a

nd n

o d

iffere

nces b

etw

een

rem

itted a

nd n

on-r

em

itted p

atients

.

Sava

ska

n

et a

l. (2

008)

[9]

P =

18

C =

22

• M

DD

fi r

st

epis

ode

• In

patient

• S

am

ple

>65 y

ears

GD

S =

9P

= 7

6

C =

77

4 w

eeks

Gro

up im

pro

vem

ent

in G

DS

at

FU

.

Neuro

psyc f

unction (

MM

SE

) sig

nifi

cantly

impro

ved o

ver

treatm

ent, b

ut

no c

orr

ela

tion

done t

o r

ela

te Δ

MM

SE

to Δ

GD

S. C

ontr

ols

only

did

baselin

e M

MS

E.

BD

, bip

ola

r depre

ssio

n;

BD

I, B

eck

Depre

ssio

n I

nve

nto

ry;

BR

MS

, B

ech–R

afa

els

en M

ela

ncholia

Scale

; C

, contr

ol;

CD

S,

Corn

ell

Depre

ssio

n S

cale

; C

GI, C

linic

al G

lobal

Impre

ssio

n;

DR

S,

Dem

entia R

ating S

cale

; D

SS

T,

Dig

it S

ym

bol S

ubstitu

tion T

ask;

DY

S,

dys

thym

ia;

FU

, fo

llow

up;

GD

S,

Geri

atr

ic D

epre

ssio

n S

cale

; H

DR

S-1

7, 1

7-item

Ham

ilton

Depre

ssio

n R

atin

g S

cale

; H

DR

S-2

1,

21-

item

Ham

ilton D

epre

ssio

n R

ating S

cale

; H

DR

S-2

4,

24-ite

m H

am

ilton D

epre

ssio

n R

ating S

cale

; M

AD

RS

, M

ontg

om

ery

–A

sberg

Depre

ssio

n R

atin

g S

cale

; M

CI, m

ild c

ognitiv

e im

pair

ment; M

DD

, m

ajo

r depre

ssiv

e d

isord

er;

MM

SE

, M

ini M

enta

l S

tate

Exa

min

ation;

P,

patient; s

chiz

.AD

, schiz

oaffective

dis

ord

er;

SLT

, S

hoppin

g L

ist

Task; T

MT-

B,

Tra

il-M

akin

g T

est–

Part

B;

UN

I, u

nip

ola

r depre

ssio

n; W

MS

-III,

Wechsle

r M

em

ory

Scale

–3rd

edn; Y

DI, Y

ale

Depre

ssio

n I

nve

nto

ry.


Two measures within the domain of executive functioning for which

there is evidence of an association with changes in depressive symptoms

are verbal and design fl uency. That is, the ease with which a person can

produce words or drawings given a certain set of rules. Verbal fl uency

tasks require patients to produce as many words as possible starting with

a certain letter (phonological) or belonging to a particular category

(semantic) in either 60 or 90 s. Design fl uency, in contrast, involves

producing as many different drawings or symbols within the same

amount of time. Mildly and severely depressed patients have shown

similar trends across treatment in verbal fl uency tasks, with performance

normalizing with successful treatment of MDD [7,8,22,31]. Two par-

ticularly strong studies directly related clinical state to change in verbal

fl uency. Among a battery of many neuropsychological measures, Beblo

et al. found that improvement in both verbal and design fl uency was the

only neuropsychological measure that was signifi cantly different

between responders and non-responders [22]. Furthermore, in their

severely depressed inpatient sample, Trichard et al. demonstrated a sig-

nifi cant correlation between improvement in mood and improvement in

verbal fl uency, while the Stroop task remained impaired, as already

described [31].

In summary, except for tests of fl uency, executive functioning/

attention has generally been shown to remain impaired during and

following treatment compared with healthy controls but shows slight

improvement if given enough time. The diverse nature of executive

functioning tasks, however, highlights the need to classify executive

functioning measures into subcategories in order to understand the pre-

cise brain mechanisms controlling each task.

Evidence of executive functioning/attention improvement in late-life

MDD is sparse. Many studies have been unsuccessful in fi nding a rela-

tionship between changes in executive functioning/attention and MDD

recovery. This includes a robust study by Butters et al. in which patients

whose MDD had not recurred at 12–14 weeks showed no improvement

in executive functioning [26]. It appears that most studies fi nd execu-

tive functioning/attention throughout late-life MDD episodes to be

relatively insensitive to response to various pharmacological treatments

over 3 months [15,27], 6 months [20] and 12 months [14]. In fact, to

our knowledge, the only study that has found signifi cant improvement

in executive functioning/attention following recovery from depression,

among improvement across a broad range of neuropsychological tasks,

was that by Beats et al. [13].

Verbal learning and memory

Despite a relatively small number of studies, a relationship between

improvement in verbal learning and memory (VLM) and improvement

in depressive symptoms is a fairly consistent fi nding. In the Biringer

et al. 2 year follow-up study, improvement in VLM was found to be

signifi cantly correlated with improvement in depressive symptoms [3].

Several studies with follow-up testing between 2 months and 2 years

after baseline have also shown VLM to improve signifi cantly more in

those who achieve remission or response to treatment compared with

those who do not [3,10,23]. These changes occurred within the context

of a comprehensive neuropsychological battery in which all other tests,

Neuropsychological changes during treatment of MDD

To make the results clearer, we have separated the study fi ndings into

four main neuropsychological domains: executive functioning/atten-

tion, verbal memory, non-verbal memory, and psychomotor speed.

Sustained attention and executive functioning

There are inconsistencies in the literature concerning the categoriza-

tion of attention and executive func tioning. Furthermore, the tasks

used to measure these functions have considerable overlap [33]. We

have, therefore, combined fi ndings from both of these neuropsycho-

logical domains. It should also be noted that although working mem-

ory is sometimes classed under the umbrella of ‘memory functions’,

we have included it in this section too.

Short-term studies suggest that various measures of attention and

executive functioning remain impaired during treatment of and recov-

ery from MDD. In a short-term study in a severely depressed sample,

Trichard et al. found no correlation between improvement in MDD and

performance on the Stroop task at 4 weeks [31]. After 2–6 months in

a moderately depressed sample, Gallagher et al. found no differences

in executive functioning/attention changes between responders and

non-responders (using spatial working memory and the Tower of Lon-

don tasks) [23]. Jaeger et al., in a sample including patients with psy-

chotic depression, found improvement in composite executive function

and composite attention scores at 6 months, but did not separate

responders and non-responders in their analysis [5]. A very much

longer-term follow-up study found a signifi cant correlation between

improvement in MDD and change in a composite score of executive

functioning at 2 years [21]. When re-analysing the results from that

study with a thorough operationalization procedure, however, the cor-

relation between improvement in composite executive functioning/

attention and mood did not remain. The recovered depressed patients

performed better in attention than in their depressed states, but still not

to the level of healthy controls [3].

Overall, the studies that found relatively stable impairment in exec-

utive functioning/attention tasks conducted the follow-up neuropsycho-

logical batteries at ≤6 months. The second study by Biringer et al. [3]

involved follow up at 2 years and found that although tasks of attention

signifi cantly improved with recovery from MDD, performance never

completely returned to normal. This conclusion is supported by studies

examining fully recovered or euthymic patients previously diagnosed

with MDD who show persistent impairment on tasks of executive func-

tioning/attention [34], even when performance on other neuropsycho-

logical tasks is comparable to healthy controls [35,36].

Twin studies offer the ability to determine whether genetic liability

to MDD is associated with neuropsychological impairment. Chris-

tensen et al. found that broad executive functioning impairment was

present before the onset of MDD in healthy twins discordant for uni-

polar MDD [37], suggesting that those at high risk of MDD have

reduced executive ability; the extent of this impairment may of course

increase during episodes of MDD.


NVLM, the relationship between the two was not examined. Vythilingam

et al. found that performance on the visual selective reminding test

improved in treatment responders (all patients were classifi ed as treat-

ment responders) even though, compared with control participants, the

depressed outpatients were not impaired on this task to begin with [10].

In a study of treatment with bupropion, Herrera-Guzman et al. found

that responders improved to a greater extent that non-responders in

NVLM after 8 weeks [28], but this was the smallest sample in the

review (responders = 12, non-responders = 8), making the fi ndings

somewhat preliminary. Larger neuropsychological studies that have

directly related change in NVLM to change in depressive symptomatol-

ogy have not produced any signifi cant fi ndings [3,22,23].

In two late-life MDD studies that tested specifi cally for NVLM

changes as opposed to VLM, performance on some but not all visu-

ospatial memory tasks nor malized to the level of controls on recovery

from MDD [12,13]. As well as the improvements in VLM discussed in

the previous section, Gallassi et al. found similar improvements in

visual memory in remitters yet, as stated earlier, remitters were not

compared with non-remitters [17].

Psychomotor speed

Studies generally suggest that psychomotor speed is unrelated to

MDD severity or clinical state in younger adult populations. Several

different measures of psychomotor speed have failed to show sensitiv-

ity to change in clinical state including the Stroop task – reaction time

[31], the Phasic Alertness Task – reaction time [22], the Digit Symbol

Substitution Task (DSST) [23], Trail-Making A [10], and the California

Computerized Assessment Package, which was developed as a special-

ized package to measure psychomotor speed [3]. Constant et al.,

however, found a signifi cant correlation between improvement in psy-

chomotor speed after 3 weeks of sertraline treatment and MDD sever-

ity [29] but at 7 weeks, after further improvement in mood, there was

still signifi cant psychomotor slowing compared with controls and no

correlation with clinical improvement. Another study showing sensitiv-

ity of psychomotor speed to treatment response, among various other

neuropsychological tasks, was conducted by Reppermund et al. [24]

using the Zahlen–Verbindungs-Test in inpatients. In that study remitters

showed signifi cant improvement in reaction time compared with non-

remitters.

Overall there are some data suggesting that psychomotor speed is

sensitive to clinical state in the younger depressed population. Clini-

cally marked psychomotor retardation is observed in adult depressed

patients and improves with successful treatment. It may be that fi ndings

from patients with clear psychomotor retardation are washed out when

means are analysed in groups of relatively less severely depressed

patients.

In late-life depressed samples it is more likely that baseline impair-

ment in psychomotor speed will be observed [42,43]. Although Beats

et al. found a broad range of improvement in many neuropsychological

domains on recovery from various pharmacological treatments, mea-

sures of reaction times were the exception and remained impaired [13].

Conversely, in their sample of late-life depressed patients, Devanand

including measures of executive functioning/attention and psychomotor

speed, were unrelated to clinical response. The studies had diverse sam-

ples of patients that differed in terms of hospitalization, severity, MDD

type, and number of episodes of MDD. All patients, however, were diag-

nosed with unipolar MDD. Measures of non-VLM (NVLM) in two of

these studies also failed to relate to clinical state [3,23]. Consistent with

these fi ndings, cross-sectional studies in patients who have fully recov-

ered from MDD, or are in their euthymic phase, have found that VLM

is unimpaired compared with healthy controls [35,36].

The Beblo et al. study stands out among the others because no asso-

ciation between VLM and MDD recovery was shown [22]. Performance

on VLM tasks remained impaired at the follow up, which varied from

1 to 3 months after baseline. A major difference between the Beblo et al.

study and those already described above involved the mean age of the

depressed samples: being 33 years [23], 36 years [3], 41 years [10], and

56 years [22].

Two studies in late-life MDD also suggest that VLM performance is

sensitive to clinical state. In a large study Doraiswamy et al. demon-

strated a signifi cant correlation between improvement in clinical state

and improvement on the Shopping List Task (also known as the

Buschke-Fuld Selective Reminding Test) after 12 weeks of treatment

[32]. Gallassi et al. showed improvement in VLM in remitters, but in

VLM tasks that required more cognitive effort (logical memory and

associated verbal learning) these patients still differed from controls

[17]. In addition, remitters were not directly compared to non-remitters

in that study.

A number of studies have shown persistence of VLM impairment in

late-life MDD populations [4,15,19,20,27], possibly relating to pro-

longed treatment responses in older populations [38]. VLM also appears

to be more severely impaired in late-life MDD patients than younger

patients [39]. O’Brien et al. found an association between impaired

memory (a composite of verbal and visual memory) and hippocampal

volume at 6 months, suggesting that in late-life MDD structural changes

may be related to persisting neuropsychological impairment [20]. A

very large follow-up study in MDD that did not compare neuropsycho-

logical function between tests, however, examined predictors of neu-

ropsychological dysfunction at baseline and at a follow-up session

several weeks later following clinical response. At follow up, length of

previous depressive history was a signifi cant predictor of memory func-

tion (paragraph learning) [40]. This may be related to structural changes,

such as reduced hippocampal volume, in MDD [41].

Non-verbal learning and memory

Of the studies investigating NVLM throughout an MDD episode,

four studies found differences in performance with changes in MDD

severity. In a study of patients with bipolar disorder and depressive

symptoms (some were subsyndromal for MDD), spatial recognition

memory showed signifi cant improvement after treatment with mifepri-

stone [8]. Wroolie et al., in a sample of depressed female subjects, also

found an improvement in immediate visual memory after treatment

with escitalopram [11]. These two studies, however, only showed group

improvements in depressive symptoms and group improvements in


symptomatology and improvement of neuropsychological function on

a continuum is preferable because this captures more of the variance in

the measures.

Time to follow up

The time between baseline and follow-up testing sessions varied

greatly between studies. Many of the studies involving neuropsycho-

logical testing were drug trials, and hence had 6–12 weeks between the

testing sessions. The importance of timing is crucial because not all

variables that remain the same over the follow-up sessions should auto-

matically be classed as trait markers of MDD. It may be that these

variables simply take longer to return to normal than those classed as

state markers.

Subtype of MDD

The issue of clinical factors such as severity of MDD, inpatient sta-

tus, presence of melancholia, comorbid anxiety and personality disor-

ders, and number of episodes of depression should, if possible, be taken

into account and at least reported [48]. Certain aspects of these factors

may affect both the profi le of neuropsychological dysfunction in MDD

and also the speed and completeness of response to treatment.

It is also likely that subtypes of MDD, such as bipolar or psychotic

depression, could have different neuropsychological profi les during treat-

ment. Table 1 lists studies in which bipolar or psychotically depressed

patients were included, but in some studies this information was not

provided. Only one study specifi cally examined bipolar depression [8],

while remaining studies that included bipolar depressed patients did not

separate the analysis into subtypes, meaning that it cannot be determined

whether there are different neuropsychological changes over time between

unipolar and bipolar depression. Regarding psychotic depression, it is

known that this subtype is associated with a more widespread neuropsy-

chological impairment [53], but we found no studies looking specifi cally

at changes in neuropsychological performance during treatment in psy-

chotic depression. Again, many studies in the review included depressed

patients with psychotic features, but did not conduct analyses to compare

neuropsychological changes in patients with non-psychotic features.

Age

Studies have suggested that the neuropsychological impairment asso-

ciated with late-life MDD is more severe than in younger depressed

patients [54], particularly in the domains of psychomotor speed [42,43]

and in verbal memory [39]. An issue in late-life studies, however, is that

there may be an important difference between early- and late-onset

MDD. Most late-life studies in the present review include a mixture of

depressed patients with early- and late-onset MDD. Because of the pos-

sible different biological origin between early- and late-onset MDD [55],

this should be taken into account when examining neuropsychological

function in this group. Another important methodological factor is the

follow-up interval. Patients with late-life MDD may take longer to

et al. found a specifi c improvement in psychomotor speed in respond-

ers compared with non-responders using the DSST [27]. Interestingly,

non-responders to sertraline actually worsened from baseline to follow

up. Doraiswamy et al. also found evidence of psychomotor sensitivity

to sertraline treatment response [32]. In their more severely depressed

sample, improvement on the DSST signifi cantly correlated with

improvement of mood. Overall, the data are more consistent in suggest-

ing a relationship between clinical response and improved psychomotor

function in late-life MDD, as might be expected from the greater inci-

dence of psychomotor retardation in this age-group.

Methodological issues of reviewed studies

Matched controls

A major problem with several studies was the lack of a matched

healthy control group. A control group is necessary when there are

repeated neuropsychological testing sessions to examine the extent to

which improvements in performance are related to symptom change,

as opposed to practice effects from repeated administration. Even if

parallel forms are used, improvement can still occur due to enhanced

learning strategies. This issue can be controlled for only if controls

perform equivalent testing sessions to the patient group.

The control group should also be appropriately matched to the

patients, bearing in mind that many demographic factors may affect

neuropsychological function. These factors include gender [44], age and

education [45], and phase of menstrual cycle [46,47]. In addition, non-

psychiatric related exclusion criteria (such as pregnancy, previous head

injury, or serious medical conditions) should be the same for patients

and controls.

Medications

The type of medication that patients and controls are taking is impor-

tant, particularly in studies recruiting patients with milder forms of

MDD whose impairment may be more subtle [48]. Research suggests

that neuropsychological impairment in MDD is not solely due to the

effects of antidepressant medication [5,49], because studies in unmed-

icated depressed patients have shown signifi cant differences in neurop-

sychological function compared with controls [50]. Some classes of

antidepressants, however, are more likely to cause neuropsychological

dysfunction, for instance, tricyclic antidepressants [51,52].

Categorization of patients by treatment outcome

A common way of analysing the relationship between change in

depressive symptomatology and change in neuropsychological function

was to compare remitters with non-remitters, or responders with non-

responders, at the end of the treatment period. The defi nition of remis-

sion, however, varies between studies, as does the mood rating scale

used. Furthermore, separating patients into remitters or non-remitters

could result in individuals who score close to the cut-off being misclas-

sifi ed [3]. In our opinion, measurement of improvement in depressive


and subject to fl oor effects. Thus, shortening or modify-ing of the tasks may be necessary. The Controlled Oral Word Association Task was the most common measure of phonological and semantic (verbal) fl uency, while design fl uency was measured with the Five-point Test [33]. The DSST produced strong fi ndings in the late-life MDD samples in the present review, and hence is our recommendation for a pure psychomotor measure. In late-life MDD studies it is important to have longer-term follow up to allow for the possibility of prolonged treat-ment response.

This review also highlighted the variability of fi ndings in neuropsychological studies of MDD and it was pro-posed that methodological issues were likely to be major contributors to these inconsistencies. We suggest that studies examining neuropsychological functioning across treatment of MDD should include matched healthy con-trols (matched for age, gender, IQ and menstrual cycle), take into account the medication status of patients and the subtype of MDD they are diagnosed with, and directly relate treatment response to changes in neuropsycholog-ical function. We believe that correlation of changes in mood rating scale scores with changes in neuropsycho-logical test scores is the optimal analysis, because it eliminates the issue of categorical misclassifi cation into responders or remitters.

Future directions

The current review has presented evidence from studies using traditional neuropsychological tasks. Increasing attention, however, has been given to emotionally valenced neuropsychological tasks in MDD, with one reviewed article fi nding evidence of sensitivity to clinical state using the emotional Stroop test [29]. Facial emotion recognition tasks may also be useful objective markers of treatment response. It has been found that depressed individuals are more likely to classify ambiguous faces as negative [56], consistent with psychological theories of MDD that emphasize the role of negative biases in information pro-cessing [57]. Furthermore, studies have begun to clarify the relationship between facial emotion recognition impair-ments and specifi c brain structures and neural pathways involved in emotion perception [58]. Harmer provided pre-liminary evidence of negative biases in facial emotion recognition in MDD norma lizing with successful treat-ment [59], supporting a review that presented indirect sup-port for facial expression perception as an objective outcome measure for treatment studies in MDD [60]. Given the promising initial fi ndings, we believe that the inclusion of a facial emotion recognition task [61] could provide useful insights into neurobiological changes occur-ring during the treatment of MDD.

respond to treatment than younger patients with MDD [38], perhaps

resulting in changes in neuropsychological function taking longer.

Long follow-up intervals, however, could be confounded by age-related

decline and by progression of a number of patients to dementia.

This issue can of course be controlled for by using an age-matched

control group.

Discussion

After an extensive literature search, we identifi ed 30 studies eligible for inclusion in this review. In adult MDD samples, verbal measures of learning and mem-ory and fl uency produced the most robust evidence of sensitivity to clinical state, with improvement in these tasks being signifi cantly related to improvement in mood in a number of comprehensive studies. Why ver-bal measures appeared to be the most sensitive is unclear, but it may be in part due to the relative ease of administering verbal compared to non-verbal neuropsy-chological tasks. Pure measures of psychomotor speed in the adult MDD samples showed some support of an association with improvement in clinical state. It should be noted that a major component of verbal fl uency, and various other timed neuropsychological measures, is psychomotor speed. Measures of executive functioning and attention tended to remain impaired across treat-ment, suggesting a more trait-like feature of these domains.

In late-life MDD the neuropsychological domain that demonstrated the clearest association with treatment response was psychomotor speed. Two studies that sup-ported this view (using correlation and responders vs non-responders as treatment outcomes) produced signifi -cant evidence of improvement in psychomotor speed with treatment response using the DSST [33], a pure measure of psychomotor speed. In contrast, verbal mem-ory and attention/executive functioning appeared to remain impaired over time.

Given the fi ndings from younger adult and late-life MDD samples, we recommend that a neuropsychological testing battery including specifi c measures of VLM, ver-bal fl uency, and psychomotor speed be used in future studies aiming to examine the relationship between mood and neuropsychological functioning in MDD. Typical measures of VLM used in this review were word list-learning tasks such as the Rey Auditory–Verbal Learning Task, the California Verbal Learning Task, and the verbal subtests of the Wechsler Memory Scale–Revised [33]. Inclusion of delayed recall and recognition components allows for a more detailed examination of VLM, but in severely depressed samples the original versions of these tasks are likely to be poorly tolerated by some patients


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In addition to focusing our attention on alternative measures that may indicate treatment response, it is also important to continue to search for reasons why neuro -psychological function is impaired in MDD. A possibility is that severe or multiple episodes of MDD may result in changes in neurobiology, giving rise to permanently impaired neuropsychological function. Thus, long-term description of the effects of multiple depressive episodes on neuropsychological function would be of great interest.

Conclusion

The present review suggests that certain tests of neu-ropsychological function may be useful indicators of treatment response in MDD. Being able to objectively examine changes in brain function during treatment may add to assessment of treatment response and potentially aid clinicians in optimizing treatment. It may also add to assessment of treatment effi cacy in trials of treatments for depression. Before this can occur, however, many more methodologically sound, large-sample studies are required to clarify the neuropsychological domains and tests most sensitive to clinical state in MDD.

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